C. elegans locomotes in an undulatory fashion, generating thrust by propagating dorsoventral bends along its body. Although central pattern generators (CPGs) are typically involved in animal locomotion, their presence in C. elegans has been questioned, mainly because there has been no evident circuit that supports intrinsic network oscillations. With a fully reconstructed connectome, the question of whether it is possible to have a CPG in the ventral nerve cord (VNC) of C. elegans can be answered through computational models. We modeled a repeating neural unit based on segmentation analysis of the connectome. We then used an evolutionary algorithm to determine the unknown physiological parameters of each neuron so as to match the features of the neural traces of the worm during forward and backward locomotion. We performed 1,000 evolutionary runs and consistently found configurations of the neural circuit that produced oscillations matching the main characteristic observed in experimental recordings. In addition to providing an existence proof for the possibility of a CPG in the VNC, we suggest a series of testable hypotheses about its operation. More generally, we show the feasibility and fruitfulness of a methodology to study behavior based on a connectome, in the absence of complete neurophysiological details.

Multiple mechanisms contribute to the generation, propagation, and coordination of the rhythmic patterns necessary for locomotion in Caenorhabditis elegans. Current experiments have focused on two possibilities: pacemaker neurons and stretch-receptor feedback. Here, we focus on whether it is possible that a chain of multiple network rhythmic pattern generators in the ventral nerve cord also contribute to locomotion. We use a simulation model to search for parameters of the anatomically constrained ventral nerve cord circuit that, when embodied and situated, can drive forward locomotion on agar, in the absence of pacemaker neurons or stretch-receptor feedback. Systematic exploration of the space of possible solutions reveals that there are multiple configurations that result in locomotion that is consistent with certain aspects of the kinematics of worm locomotion on agar. Analysis of the best solutions reveals that gap junctions between different classes of motorneurons in the ventral nerve cord can play key roles in coordinating the multiple rhythmic pattern generators.

No abstract

Multiple mechanisms contribute to the generation, propagation, and coordination of 8 rhythmic patterns necessary for locomotion in Caenorhabditis elegans. Current experiments have 9 focused on two possibilities: pacemaker neurons and stretch-receptor feedback. Here, we focus on 10 whether locomotion behavior can be produced by a chain of network oscillators in the ventral 11 nerve cord. We use a simulation model to demonstrate that a repeating neural circuit identified in 12 the worm's connectome can be chained together to drive forward locomotion on agar in a 13 neuromechanical model of the nematode, in the absence of pacemaker neurons or 14 stretch-receptor feedback. Systematic exploration of the space of possible solutions reveals that 15 there are multiple configurations that result in locomotion that match the kinematics of the worm 16 on agar. Analysis of the best solutions reveals that gap junctions between different classes of 17 motoneurons are likely to play key roles in coordinating oscillations along the ventral nerve cord. 18 19 40 1 of 24 Manuscript submitted to eLife that modulate C. elegans locomotion (Tavernarakis et al., 1997), as well as evidence of a direct 41 relationship between body curvature and neural activity (Wen et al., 2012). However, coordinated 42 rhythmic patterns can also be produced internally, while remaining open to modulation through 43 external contributions. Central pattern generators (CPGs) are known to be involved in a wide variety 44 of behaviors in a number of different organisms, including insect flight, swimming in molluscs, gut 45 movements in crustaceans, and swimming and respiration in vertebrates (Marder and Bucher, 2001; 46 Goulding, 2009; Katz, 2016; Arshavsky et al., 2016; Dasen, 2018; Minassian et al., 2017). In a CPG, 47 the rhythmic pattern can be generated through the intrinsic oscillatory properties of pacemaker 48 neurons or it can emerge from the interaction of networks of non-oscillatory neurons (Goulding, 49 2009). Recent experiments have provided support for the role of intrinsic oscillations in C. elegans 50 locomotion (Gao et al., 2018; Fouad et al., 2018; Xu et al., 2018). Although the work attributes the 51 source of these rhythm generators to pacemaker neurons, the evidence provided does not discard 52 the possibility of network oscillators (Wen et al., 2018). 53 It is increasingly acknowledged that simulation models play an important role in elucidating 54 how brain-body-environment systems produce behavior (Ijspeert, 2008; Abbott, 2008; Izquierdo, 55 2018). In C. elegans, there has been an surge of theoretical work focused on understanding the 56 neuromechanical basis of locomotion. Several computational models have demonstrated that 57 proprioception alone can be used to generate rhythmic patterns and propagate them along the 58 body (Niebur and Erdös, 1991; Karbowski et al., 2008; Boyle, 2009; Mailler et al., 2010; Wen et al., 59 2012; Izquierdo and Beer, 2018; Fieseler et al., 2018; Gleeson et al., 2018). There have also been a 60 number of m...

Autonomously firing GABAergic neurons in the external globus pallidus (GPe) form a local synaptic network. In slices, most GPe neurons receive a continuous inhibitory synaptic barrage from 1-2 presynaptic GPe neurons. We measured the barrage's effect on the firing rate and regularity of GPe neurons in male and female mice using perforated patch recordings. Silencing the firing of parvalbumin-positive (PV+) GPe neurons by activating genetically expressed Archaerhodopsin current increased the firing rate and regularity of PV- neurons. In contrast, silencing Npas1+ GPe neurons with Archaerhodopsin had insignificant effects on Npas1- neuron firing. Blocking spontaneous GABAergic synaptic input with gabazine reproduced the effects of silencing PV+ neuron firing on the firing rate and regularity of Npas1+ neurons and had similar effects on PV+ neuron firing. To simulate the barrage, we constructed conductance waveforms for dynamic clamp based on experimentally measured inhibitory postsynaptic conductance trains from 1-2 unitary local connections. The resulting inhibition replicated the effect on firing seen in the intact active network in the slice. We then increased the number of unitary inputs to match estimates of local network connectivityin vivo. As few as 5 unitary inputs produced large increases in firing irregularity. The firing rate was also reduced initially, but PV+ neurons exhibited a slow spike frequency adaptation that partially restored the rate despite sustained inhibition. We conclude that the irregular firing pattern of GPe neuronsin vivois largely due the ongoing local inhibitory synaptic barrage produced by the spontaneous firing of other GPe neurons.SIGNIFICANCE:Functional roles of local axon collaterals in the external globus pallidus (GPe) have remained elusive due to difficulty in isolating local inhibition from other GABAergic inputsin vivo, and in preserving the autonomous firing of GPe neurons and detecting their spontaneous local inputs in slices. We used perforated patch recordings to detect spontaneous local inputs during rhythmic firing. We found that the autonomous firing of single presynaptic GPe neurons produces inhibitory synaptic barrages that significantly alter the firing regularity of other GPe neurons. Our findings suggest that although GPe neurons receive input from only a few other GPe neurons, each local connection has a large impact on their firing.